Cross-recognition of N-formylmethionine peptides is a general characteristic of H2-M3-restricted CD8+ T cells.
ABSTRACT H2-M3-restricted CD8+ T cells can exhibit cross-reactivity to different bacterially derived N-formylmethionine peptides. The extent of this promiscuity is unclear. We deleted the nonredundant fMIVTLF epitope and found that Listeria monocytogenes still primed fMIVTLF-specific T cells. Thus, cross-reactivity appears to be a more general characteristic of H2-M3-restricted T cells.
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ABSTRACT: CD4 T cells play important roles in adaptive immune responses. Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for selection, as shown in mouse models. However, increasing evidence suggests that CD4 T cell selection mediated by hematopoietic cells such as thymocytes also occurs in humans as well as in mouse models. Thymocyte-selected CD4 T cells (T-CD4 T cells) are shown to be different from epithelial cell-selected CD4 T cells (E-CD4) in many aspects including developmental requirements and functional characteristics. In this study, the strength of TCR signaling necessary for T-CD4 T cell development and role of T-CD4 T cells during bacteria infection was investigated. In contrast to E-CD4 T cells, T-CD4 T cells were selected more efficiently when TCR signaling was weakened. In addition, T-CD4 T cell development relied on the presence of the promyelocytic leukemia zinc finger protein, a transcription factor essential for invariant NKT cell generation. The distinct developmental process mediated by thymocytes resulted in T-CD4 T cells possessing the suppressive function. Instead of promoting host immunity as E-CD4 T cells do, T-CD4 T cells suppressed anti-Listerial responses, evidenced by the reduced frequency and cytotoxicity of Listeria-specific CD8 T cells during both the primary and the memory immune response. Studies in this dissertation revealed the novel suppressive function of T-CD4 T cells, which is most likely caused by the differential signaling delivered during thymocyte-thymocyte interactions in the thymus.
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ABSTRACT: Not embargoed. Vita. Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. Bibliography: 114-132.
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ABSTRACT: The major histocompatibility complex (MHC) class Ib molecule H2-M3 primes the rapid expansion of CD8+ T cells by presenting N-formylated bacterial peptides. However, the signifi cance of H2-M3-restricted T cells in host defense against bacteria is unclear. We generated H2-M3-defi cient mice to investigate the role of H2-M3 in immunity against Listeria monocytogenes (LM), a model intracellular bacterial pathogen. H2-M3-defi cient mice are impaired in early bacterial clearance during primary infection, with diminished LM-specifi c CD8+ T cell responses and compromised innate immune functions. Although H2-M3-restricted CD8+ T cells constitute a signifi cant proportion of the anti-listerial CD8+ T cell repertoire, the kinetics and magnitude of MHC class Ia-restricted T cell responses are not altered in H2-M3-defi cient mice. The fact that MHC class Ia-restricted responses cannot compensate for the H2-M3-mediated immunity suggests a nonredundant role of H2-M3 in the protective immunity against LM. Thus, the early H2-M3-restricted response temporally bridges the gap between innate and adaptive immune responses, subsequently affecting the function of both branches of the immune system.